The Role of Proline-Proline-Glutamic Acid (PPE) Proteins in Mycobacterium tuberculosis Virulence: Mechanistic Insights and Therapeutic Implications

Abstract

For decades, tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), has remained a global health challenge. Central to this issue are the proline-proline-glutamic acid (PPE) proteins, which play a pivotal role in the pathogenesis and persistence of MTB. This article explores the molecular mechanisms of PPE proteins and their roles in facilitating MTB's evasion of the host's immune system while enhancing virulence and transmission. Focusing on the structural and functional aspects of PPE proteins, this review provides a detailed analysis of antigenic variation, a crucial mechanism allowing MTB to elude immune detection. It also probes the genetic diversity of these PPE proteins and their complex interactions with host immunity, offering insights into the challenges they pose for therapeutic development. This review delves into the potential of targeting PPE proteins in novel therapeutic strategies, discussing the prospects of drug and vaccine development. The evidence reviewed in this article underscores the pressing need for innovative approaches to combat TB, especially in the face of increasing drug resistance. Ultimately, this review article highlights the untapped potential of PPE proteins in revolutionizing TB treatment, paving the way for breakthroughs in drug and vaccine development.

Keywords: clinical drug development; mtb (mycobacterium tuberculosis); ppe protein; tb; tuberculosis.

Figure 1. Sequential steps by which Mycobacterium tuberculosis evades the host immune system via PPE proteins. The flowchart begins with the pathogen-expressing PPE proteins, which modulate the immune response. These proteins interact with host immune cells, such as macrophages and dendritic cells, altering their function and inhibiting immune response. Consequently, the pathogen survives and proliferates within the host, potentially resulting in chronic infection or latency. The pathogen can be transmitted to new hosts, completing the infectious cycle. The pathogen adapts and develops mechanisms to further evade the immune response.

PPE: proline-proline-glutamic acid Created with BioRender.com.

Figure 2. Progression of Mycobacterium tuberculosis infection and role of PPE proteins. (1) PPE proteins aid in the initial survival of the bacteria. Following alveolar deposition, bacilli encounter and infect macrophages. (2) PPE proteins facilitate immune evasion. The subsequent immune response leads to the formation of granulomas. (3) PPE proteins contribute to a latent infection. (4) The potential reactivation of MTB. (5) Active TB: PPE proteins modify the bacterial phenotype to promote replication and disease progression. Damaged respiratory epithelial cells are depicted in the background, indicating the pathological effect of an active infection. While indirectly related to MTB pathogenesis, the allergen icon alludes to external factors that can exacerbate lung damage and influence the course of the disease.

MTB: Mycobacterium tuberculosis; PPE: proline-proline-glutamic acid; TB: tuberculosis Created with BioRender.com.